Silencing of the Drosophila ortholog of SOX5 in heart leads to cardiac dysfunction as detected by optical coherence tomography
Silencing of the Drosophila ortholog of SOX5 in heart leads to cardiac dysfunction as detected by optical coherence tomography
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DOI：
10.1093/hmg/ddt230
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发表时间：
2013-09-15
影响因子：
3.5
通讯作者：
Tanzi, Rudolph E.
中科院分区：
文献类型：
--
作者：
Li, Airong;Ahsen, Osman O.;Tanzi, Rudolph E.
SRY相关的HMG盒5（SOX 5）基因编码SOX家族转录因子的成员。最近，全基因组关联研究表明SOX 5是四种心脏相关内表型易感性的候选基因：较高的静息心率（HR），心电图PR间期，心房颤动和左心室质量。我们已经确定，人类SOX 5有一个高度保守的果蝇直系同源物，Sox102F，并采用转基因果蝇模型定量测量成年果蝇的心脏功能。为此，我们已经开发了一种高速和超高分辨率的光学相干断层成像系统，该系统能够在各种心动周期内对心管进行快速横截面成像，用于测量心脏结构和动力学参数，例如HR，心腔的尺寸和面积，心壁厚度和壁速度。我们已经发现，Sox102F的沉默导致HR、心腔大小和心壁速度的显著降低，以及心壁厚度的显著增加，这伴随着成年果蝇中肌原纤维结构的破坏。此外，Sox102F在翅中的沉默导致L2、L3和翅边缘静脉增加，Wnt信号通路的中心组分wingless的表达增加且紊乱。总的来说，Sox102F的沉默导致严重的心脏功能障碍和结构缺陷，并破坏了果蝇的Wnt信号转导。这暗示了SOX 5在心脏中的重要功能作用，并表明SOX 5水平的改变可能有助于多种心脏疾病或性状的发病机制。
The SRY-related HMG-box 5 (SOX5) gene encodes a member of the SOX family of transcription factors. Recently, genome-wide association studies have implicated SOX5 as a candidate gene for susceptibility to four cardiac-related endophenotypes: higher resting heart rate (HR), the electrocardiographic PR interval, atrial fibrillation and left ventricular mass. We have determined that human SOX5 has a highly conserved Drosophila ortholog, Sox102F, and have employed transgenic Drosophila models to quantitatively measure cardiac function in adult flies. For this purpose, we have developed a high-speed and ultrahigh-resolution optical coherence tomography imaging system, which enables rapid cross-sectional imaging of the heart tube over various cardiac cycles for the measurement of cardiac structural and dynamical parameters such as HR, dimensions and areas of heart chambers, cardiac wall thickness and wall velocities. We have found that the silencing of Sox102F resulted in a significant decrease in HR, heart chamber size and cardiac wall velocities, and a significant increase in cardiac wall thickness that was accompanied by disrupted myofibril structure in adult flies. In addition, the silencing of Sox102F in the wing led to increased L2, L3 and wing marginal veins and increased and disorganized expression of wingless, the central component of the Wnt signaling pathway. Collectively, the silencing of Sox102F resulted in severe cardiac dysfunction and structural defects with disrupted Wnt signaling transduction in flies. This implicates an important functional role for SOX5 in heart and suggests that the alterations in SOX5 levels may contribute to the pathogenesis of multiple cardiac diseases or traits.